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Belousov R, Berger F, Hudspeth AJ
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Volterra-series approach to stochastic nonlinear dynamics: The Duffing oscillator driven by white noise

PHYSICAL REVIEW E 2019 APR 5; 99(4):? Article 042204
The Duffing oscillator is a paradigm of bistable oscillatory motion in physics, engineering, and biology. Time series of such oscillations are often observed experimentally in a nonlinear system excited by a spontaneously fluctuating force. One is then interested in estimating effective parameter values of the stochastic Duffing model from these observations-a task that has not yielded to simple means of analysis. To this end we derive theoretical formulas for the statistics of the Duffing oscillator's time series. Expanding on our analytical results, we introduce methods of statistical inference for the parameter values of the stochastic Duffing model. By applying our method to time series from stochastic simulations, we accurately reconstruct the underlying Duffing oscillator. This approach is quite straightforward-similar techniques are used with linear Langevin models-and can be applied to time series of bistable oscillations that are frequently observed in experiments.
Zeevi D, Korem T, Godneva A, Bar N, Kurilshikov A, Lotan-Pompan M, Weinberger A, Fu JY, Wijmenga C, Zhernakova A, Segal E
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Structural variation in the gut microbiome associates with host health

NATURE 2019 APR 4; 568(7750):43-48
Differences in the presence of even a few genes between otherwise identical bacterial strains may result in critical phenotypic differences. Here we systematically identify microbial genomic structural variants (SVs) and find them to be prevalent in the human gut microbiome across phyla and to replicate in different cohorts. SVs are enriched for CRISPR-associated and antibiotic-producing functions and depleted from housekeeping genes, suggesting that they have a role in microbial adaptation. We find multiple associations between SVs and host disease risk factors, many of which replicate in an independent cohort. Exploring genes that are clustered in the same SV, we uncover several possible mechanistic links between the microbiome and its host, including a region in Anaerostipes hadrus that encodes a composite inositol catabolism-butyrate biosynthesis pathway, the presence of which is associated with lower host metabolic disease risk. Overall, our results uncover a nascent layer of variability in the microbiome that is associated with microbial adaptation and host health.
Zhu XG, Puthenveedu SN, Shen YH, La K, Ozlu C, Wang T, Klompstra D, Gultekin Y, Chi JY, Fidelin J, Peng T, Molina H, Hang HC, Min W, Birsoy K
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CHP1 Regulates Compartmentalized Glycerolipid Synthesis by Activating GPAT4

MOLECULAR CELL 2019 APR 4; 74(1):45-58.e7
Cells require a constant supply of fatty acids to survive and proliferate. Fatty acids incorporate into membrane and storage glycerolipids through a series of endoplasmic reticulum (ER) enzymes, but how these enzymes are regulated is not well understood. Here, using a combination of CRISPR-based genetic screens and unbiased lipidomics, we identified calcineurin B homologous protein 1 (CHP1) as a major regulator of ER glycerolipid synthesis. Loss of CHP1 severely reduces fatty acid incorporation and storage in mammalian cells and invertebrates. Mechanistically, CHP1 binds and activates GPAT4, which catalyzes the initial rate-limiting step in glycerolipid synthesis. GPAT4 activity requires CHP1 to be N-myristoylated, forming a key molecular interface between the two proteins. Interestingly, upon CHP1 loss, the peroxisomal enzyme, GNPAT, partially compensates for the loss of ER lipid synthesis, enabling cell proliferation. Thus, our work identifies a conserved regulator of glycerolipid metabolism and reveals plasticity in lipid synthesis of proliferating cells.
Caskey M, Klein F, Nussenzweig MC
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Broadly neutralizing anti-HIV-1 monoclonal antibodies in the clinic

NATURE MEDICINE 2019 APR; 25(4):547-553
Combination anti-retroviral therapy (ART) has revolutionized the treatment and prevention of HIV-1 infection. Taken daily, ART prevents and suppresses the infection. However, ART interruption almost invariably leads to rebound viremia in infected individuals due to a long-lived latent reservoir of integrated proviruses. Therefore, ART must be administered on a life-long basis. Here we review recent preclinical and clinical studies suggesting that immunotherapy may be an alternative or an adjuvant to ART because, in addition to preventing new infections, anti-HIV-1 antibodies clear the virus, directly kill infected cells and produce immune complexes that can enhance host immunity to the virus.
Graham WV, He WQ, Marchiando AM, Zha JM, Singh G, Li HS, Biswas A, Ong MLDM, Jiang ZH, Choi WS, Zuccola H, Wang YT, Griffith J, Wu JS, Rosenberg HJ, Wang YM, Snapper SB, Ostrov D, Meredith SC, Miller LW, Turner JR
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Intracellular MLCK1 diversion reverses barrier loss to restore mucosal homeostasis

NATURE MEDICINE 2019 APR; 25(4):690-700
Epithelial barrier loss is a driver of intestinal and systemic diseases. Myosin light chain kinase (MLCK) is a key effector of barrier dysfunction and a potential therapeutic target, but enzymatic inhibition has unacceptable toxicity. Here, we show that a unique domain within the MLCK splice variant MLCK1 directs perijunctional actomyosin ring (PAMR) recruitment. Using the domain structure and multiple screens, we identify a domain-binding small molecule (divertin) that blocks MLCK1 recruitment without inhibiting enzymatic function. Divertin blocks acute, tumor necrosis factor (TNF)-induced MLCK1 recruitment as well as downstream myosin light chain (MLC) phosphorylation, barrier loss, and diarrhea in vitro and in vivo. Divertin corrects barrier dysfunction and prevents disease development and progression in experimental inflammatory bowel disease. Beyond applications of divertin in gastrointestinal disease, this general approach to enzymatic inhibition by preventing access to specific subcellular sites provides a new paradigm for safely and precisely targeting individual properties of enzymes with multiple functions.
Silva HM, Bafica A, Rodrigues-Luiz GF, Chi J, Santos PDA, Reis BS, van Konijnenburg DPH, Crane A, Arifa RDN, Martin P, Mendes DAGB, Mansur DS, Torres CJ, Cadwell K, Cohen P, Mucida D, Lafaille JJ
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Vasculature-associated fat macrophages readily adapt to inflammatory and metabolic challenges

JOURNAL OF EXPERIMENTAL MEDICINE 2019 APR; 216(4):786-806
Tissue-resident macrophages are the most abundant immune cell population in healthy adipose tissue. Adipose tissue macrophages (ATMs) change during metabolic stress and are thought to contribute to metabolic syndrome. Here, we studied ATM subpopulations in steady state and in response to nutritional and infectious challenges. We found that tissue-resident macrophages from healthy epididymal white adipose tissue (eWAT) tightly associate with blood vessels, displaying very high endocytic capacity. We refer to these cells as vasculature-associated ATMs (VAMs). Chronic high-fat diet (HFD) results in the accumulation of a monocyte-derived CD11c(+)CD64(+ )double-positive (DP) macrophage eWAT population with a predominant anti-inflammatory/detoxifying gene profile, but reduced endocytic function. In contrast, fasting rapidly and reversibly leads to VAM depletion, while acute inflammatory stress induced by pathogens transiently depletes VAMs and simultaneously boosts DP macrophage accumulation. Our results indicate that ATM populations dynamically adapt to metabolic stress and inflammation, suggesting an important role for these cells in maintaining tissue homeostasis.
Julg B, Dee L, Ananworanich J, Barouch DH, Bar K, Caskey M, Colby DJ, Dawson L, Dong KL, Dube K, Eron J, Frater J, Gandhi RT, Geleziunas R, Goulder P, Hanna GJ, Jefferys R, Johnston R, Kuritzkes D, Li JZ, Likhitwonnawut U, van Lunzen J, Martinez-Picado J, Miller V, Montaner LJ, Nixon DF, Palm D, Pantaleo G, Peay H, Persaud D, Salzwedel J, Salzwedel K, Schacker T, Sheikh V, Sogaard OS, Spudich S, Stephenson K, Sugarman J, Taylor J, Tebas P, Tiemessen CT, Tressler R, Weiss CD, Zheng L, Robb ML, Michael NL, Mellors JW, Deeks SG, Walker BD
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Recommendations for analytical antiretroviral treatment interruptions in HIV research trials-report of a consensus meeting

LANCET HIV 2019 APR; 6(4):E259-E268
Analytical antiretroviral treatment interruption (ATI) is an important feature of HIV research, seeking to achieve sustained viral suppression in the absence of antiretroviral therapy (ART) when the goal is to measure effects of novel therapeutic interventions on time to viral load rebound or altered viral setpoint. Trials with ATIs also intend to determine host, virological, and immunological markers that are predictive of sustained viral control off ART. Although ATI is increasingly incorporated into proof-of-concept trials, no consensus has been reached on strategies to maximise its utility and minimise its risks. In addition, differences in ATI trial designs hinder the ability to compare efficacy and safety of interventions across trials. Therefore, we held a meeting of stakeholders from many interest groups, including scientists, clinicians, ethicists, social scientists, regulators, people living with HIV, and advocacy groups, to discuss the main challenges concerning ATI studies and to formulate recommendations with an emphasis on strategies for risk mitigation and monitoring, ART resumption criteria, and ethical considerations. In this Review, we present the major points of discussion and consensus views achieved with the goal of informing the conduct of ATIs to maximise the knowledge gained and minimise the risk to participants in clinical HIV research.
Indiani C, Sauve K, Raz A, Abdelhady W, Xiong YQ, Cassino C, Elayer AS, Schuch R
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The Antistaphylococcal Lysin, CF-301, Activates Key Host Factors in Human Blood To Potentiate Methicillin-Resistant Staphylococcus aureus Bacteriolysis

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 2019 APR; 63(4):? Article e02291-18
Bacteriophage-derived lysins are cell-wall-hydrolytic enzymes that represent a potential new class of antibacterial therapeutics in development to address burgeoning antimicrobial resistance. CF-301, the lead compound in this class, is in clinical development as an adjunctive treatment to potentially improve clinical cure rates of Staphylococcus aureus bacteremia and infective endocarditis (IE) when used in addition to antibiotics. In order to profile the activity of CF-301 in a clinically relevant milieu, we assessed its in vitro activity in human blood versus in a conventional testing medium (cation-adjusted Mueller-Hinton broth [caMHB]). CF-301 exhibited substantially greater potency (32 to >= 100-fold) in human blood versus caMHB in three standard microbiologic testing formats (e.g., broth dilution MICs, checkerboard synergy, and time-kill assays). We demonstrated that CF-301 acted synergistically with two key human blood factors, human serum lysozyme (HuLYZ) and human serum albumin (HSA), which normally have no nascent antistaphylococcal activity, against a prototypic methicillin-resistant S. aureus (MRSA) strain (MW2). Similar in vitro enhancement of CF-301 activity was also observed in rabbit, horse, and dog (but not rat or mouse) blood. Two well-established MRSA IE models in rabbit and rat were used to validate these findings in vivo by demonstrating comparable synergistic efficacy with standard-of-care anti-MRSA antibiotics at >= 100-fold lower lysin doses in the rabbit than in the rat model. The unique properties of CF-301 that enable bactericidal potentiation of antimicrobial activity via activation of "latent" host factors in human blood may have important therapeutic implications for durable improvements in clinical outcomes of serious antibiotic-resistant staphylococcal infections.
Galea S, Vaughan R
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Tradeoffs Between Equity and Efficiency at the Heart of Population Health Science: A Public Health of Consequence, April 2019

AMERICAN JOURNAL OF PUBLIC HEALTH 2019 APR; 109(4):541-542
Caskey M
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Delivery of anti-HIV bNAbs by viral vectors

LANCET HIV 2019 APR; 6(4):E207-E208